Discovery of Potent and Selective FABP4/5 Inhibitors with an Isoquinolone Scaffold as Potential Therapeutics for Inflammation-Related Diseases.

Fatty acid-binding proteins 4 (FABP4) and 5 (FABP5) have emerged as promising therapeutic targets for inflammation-related diseases. Herein, we report a series of potent and selective FABP4/5 inhibitors featuring an isoquinolone scaffold through scaffold hopping of RO6806051, a dual FABP4/5 inhibitor. Among these, Y18 was identified as the most promising compound, exhibiting potent inhibitory activity with Ki values of 0.41 and 2.53 μM for FABP4 and FABP5, respectively. Notably, Y18 achieves significantly improved selectivity over FABP3 (Ki = 59.72 μM) compared to RO6806051, along with favorable pharmacokinetic properties, including high oral exposure and acceptable bioavailability. Oral administration of Y18 exhibited significant anti-inflammatory effects and attenuated LPS-induced liver injury. As an anti-inflammatory compound, Y18 demonstrates an excellent safety profile with low hERG inhibition and an LD50 value greater than 2000 mg/kg. Taken together, Y18 represents a promising dual FABP4/5 inhibitor candidate for the treatment of inflammation-related diseases.